Acute motor axonal neuropathy and multifocal motor neuropathy: More in common than not

The recognition of continuity among different conditions is helpful when trying to make sense of the pathophysiology and nosology of disorders that share similarities in their clinical presentation. In the October issue, Uncini and colleagues discuss the common pathogenic mechanism that is shared by multifocal motor neuropathy (MMN) and the axonal variants of Guillain–Barré syndrome (GBS), acute motor axonal neuropathy (AMAN) and acute motor-sensory neuropathy (AMSAN).1 The authors acknowledge differences between the 3 conditions, primarily the temporal profile and degree of sensory involvement, but they choose to highlight the similarities they share, which shed some light on the underlying pathophysiology of each condition. Here, I complement their opinion from my viewpoint. The anti-ganglioside antibodies and the role they play in the pathogenesis of AMAN, AMSAN, and most likely MMN is central to discussions linking this group of disorders. There has been much debate as to whether anti-ganglioside antibodies are primary autoantibodies that cause neuropathies or are secondary phenomena resulting from nerve injury. However, the following findings suggest that anti-ganglioside antibodies are likely to have a pathogenic role: (i) following intramuscular administration of a mixture of bovine brain gangliosides including GM1, GD1a, or GM2, patients went on to develop GBS or a motor neuron diseaselike disorder,2, 3 and immunoglobulin M (IgM) anti-GM2 antibodies from a patient with a motor neuron disease-like disorder killed a GM2-enriched neuroblastoma cell line in the presence of complement4; (ii) patients have also developed peripheral neuropathy associated with the syndrome of inappropriate antidiuretic hormone after intravenous infusions of a monoclonal antibody against ganglioside GD2,5 and an immunohistochemical study using the anti-GD2 antibody confirmed strong expression of GD2 in peripheral nerves and posterior pituitary6; (iii) active immunization of rabbits with GM1 or GD1b induced the development of AMAN or acute sensory ataxic neuropathy7, 8; and (iv) passive transfer to mice of anti-GM1 or -GD1a antibodies produced AMAN models.9, 10 This evidence supports the idea that acute and chronic neuropathies associated with anti-GM1 antibodies share a similar disease process involving the same target molecule, despite the presence of different immunoglobulin isotypes, immunoglobulin G (IgG) or IgM. In animal models, anti-ganglioside antibodies bound to the peripheral nerves, where GM1 and GD1a are highly expressed at the nodes of Ranvier, and complement was activated in situ.11, 12 The autoimmune attack resulted in disappearance of voltage-gated sodium channel clusters and disruption of axo-glial junctions, which could produce nerve conduction block. This has been confirmed in a recent study where monoclonal anti-GD1a antibody injected into rat sciatic nerves caused deposition of the antibody and complement products on the nodal axolemma, disruption of clusters of nodal and paranodal molecules predominantly in motor nerves, and induced early reversible motor nerve conduction block.13 In more severely damaged nerves, Wallerian-like degeneration occurred in rabbit and mouse models.9, 12 The animal experiments have supported the clinical observations that pathophysiological continuity between conduction block and axonal degeneration exists, as discussed below. In 1986, Feasby and colleagues described patients with "an acute axonal form of Guillain–Barré polyneuropathy" who demonstrated both motor and sensory impairment.14 A few years after the findings of IgM anti-GM1 antibodies in a motor neuron disease-like disorder or MMN,15, 16 we found IgG anti-GM1 antibodies in patients with axonal GBS following Campylobacter jejuni enteritis, who presented with pure motor dysfunction.17 In 1991, Griffin's group reported the "Chinese paralytic syndrome" as a new clinical entity distinct from GBS.18 However, we believed the condition was similar to axonal GBS subsequent to C. jejuni enteritis in Japan.19 This was followed by a proposed new term "AMAN," an axonal variant of GBS, by Griffin's group in 1993.20 They later reported cases of axonal GBS presenting with both motor and sensory impairment, and proposed another term, "AMSAN."21 AMAN and AMSAN share common IgG anti-GM1 and -GD1a autoantibodies.22 Immunization of rabbits with GM1 induced development of not only AMAN but also AMSAN.13 These findings support the idea that AMAN and AMSAN are part of the spectrum of a single type of immune attack on axons, which was suggested by Griffin et al.21 In keeping with this, Uncini's group demonstrated that sensory fibers were often involved subclinically in AMAN.23 To avoid confusion and "splits," GBS is best simply classified electrophysiologically into acute inflammatory demyelinating polyneuropathy and AMAN.24 Kuwabara et al. reported some patients with AMAN associated with IgG anti-GM1 antibodies who showed rapid resolution of conduction slowing and block in the absence of remyelinating electrophysiologic features suggesting that conduction failure was caused by impaired physiologic conduction at the nodes of Ranvier rather than demyelination.25 In 2003, Uncini's group proposed "acute motor conduction block neuropathy" associated with IgG anti-GM1 or -GD1a antibodies as a new GBS variant,26 resulting in further "splits," which arguably is not necessary.27 Acute conduction block neuropathy, AMAN, and AMSAN are part of a spectrum of the same disease and could be simply classified as AMAN. Frequent presence of conduction block in AMAN patients and the coexistence of reversible conduction block and axonal degeneration in a single patient with AMAN support this proposal.28, 29 To better understand the pathophysiological continuity between conduction block and axonal degeneration, the concept of "nodo-paranodopathy" in AMAN is currently proposed by Uncini and myself.30 Although Uncini and colleagues propose the possibility of an acute-onset of MMN or an overlap between MMN and AMAN,1 robust evidence in support of this is lacking. However, there are immunological and neurophysiological similarities between MMN and AMAN, as the authors discuss.1 The underlying mechanism of MMN is unclear, but in certain patients, IgM autoantibodies against GM1 may activate complement components and cause pathological changes at the nodes and paranodes, producing conduction block. Intravenous immunoglobulin is effective for MMN as well as GBS, which may be caused by inhibition of IgM anti-GM1 antibody-mediated complement activation at the nodes and paranodes.31 At least 1 patient with MMN had IgM anti-GM1b, but not -GM1, antibodies; whereas, some patients with AMAN also have IgG anti-GM1b antibodies.32 MMN is characterized by conduction block, but several investigators have reported cases of MMN without conduction block associated with IgM anti-GM1 antibodies.33 In AMAN, we know that patients can present with or without conduction block.28 Moreover, a patient with chronic motor axonal neuropathy associated with IgM anti-GM1 antibodies, who might have MMN without conduction block, showed IgM deposition at the nodes and periaxonal macrophages in motor nerves,34 which is a characteristic pathological feature of AMAN.20 This latter finding provides evidence that immunopathological continuity exists between AMAN and MMN. In conclusion, some evidence has emerged that there are pathophysiological similarities, but not always clinical continuity, between AMAN and MMN. I thank Dr. Nortina Shahrizaila (Department of Medicine, University of Malaya) for her helpful edits.